Eosinophils are tissue dwelling hematopoietic cell types that play a role in parasitic immunity and allergic disease, such as asthma (Kita et al. 2003). Activated eosinophils secrete toxic basic proteins such as Major Basic Protein (MBP) which are postulated to cause bronchial hyperreactivity, damage of the bronchial mucosa, and remodeling of the airways. Knockout mice with no eosinophils have been shown to lack hallmarks of asthma such as airway hyperresponsiveness, tissue remodeling, and mucous metaplasia (Lee et al. 2004, Humbles et al. 2004).
Eosinophils develop in the bone marrow from hematopoietic stem cells and migrate mainly to the gut or to sites of inflammation. Eosinophils, neutrophils and monocytes have a common progenitor in the myeloid pathway of development. The interplay of several transcription factors, including GATA-1, PU.1, and the CCAAT enhancer binding proteins, c/EBPα and ε, are important to eosinophil development (McNagny et al. 2002, Nerlov et al. 1998, Hirasawa et al. 2002, Zhang et al. 19997). High levels of PU.1 specify myeloid differentiation by antagonizing GATA-1 in the earliest stages of stem cell commitment (Nerlov et al. 1998). In particular, a high affinity GATA-1 binding site within the GATA-1 promoter appears to be critical for eosinophil development; deletion of this binding site in mice specifically abolishes the entire eosinophil lineage (Okazaki et al. 2002). During later stages of eosinophil development, an intermediate level of GATA-1 in synergy with PU.1 directs the formation of the eosinophil lineage by activating dual binding sites in MBP (Du et al. 2002, Gombart et al. 2003, Yamaguchi et al. 1998). GATA-1 also activates the eotaxin receptor CC chemokine receptor-3 promoter and the IL-5Rα gene (Zimmerman et al. 2005). The CCAAT enhancer binding protein, c/EBPα, is important in early myeloid development, whereas c/EBPε plays a later role in granulocyte lineage (Yamanaka et al. 1997). Mice knockouts of c/EBPε affect both neutrophil and eosinophil development at the myelocyte to metamyelocyte stage (Yamanaka et al. 1997). Other genes involved in eosinophil development include the helix-loop-helix transcription factors, Id 1 and 2, and FOG (Friend of GATA). FOG inhibits eosinophil development by interaction with GATA-1 (Querfurth et al. 2000). Id 1 inhibits eosinophil development whereas Id 2 enhances both neutrophil and eosinophil development (Buitenhuis et al. 2005). All of these transcription factors are used in general myeloid development; eosinophil development is regulated by fine tuning of expression levels of individual transcription factors.
The complex interplay of transcription factors is influenced by the cytokines IL-3, GM-CSF and particularly the Th2 cytokine, IL-5. CD34+ hematopoietic cells cultured in IL-5 are exclusively eosinophils after several weeks of culture (Ema et al. 1990). Furthermore, transgenic mice over-expressing IL-5 have a massive eosinophilia, including infiltration into nearly all organ systems (Lee et al. 1997, Dent et al. 1990, Tominaga et al. 1991). However, mice knockouts for IL-5 still have basal levels of eosinophils but do not develop eosinophilia when infected by helminthes or challenged with aeroallergen (Kopf et al. 1996, Foster et al. 1996). Inhalation of IL-5 in human asthmatics causes increased eosinophil numbers and airway hyperreactivity (Kitagaki et al. 1997, Shi et al. 1998). Furthermore, a subset of mouse bone marrow cells expressing the IL-5Rα are eosinophil progenitors (Iwasaki et al. 2005). Therefore, IL-5 is the most important cytokine in eosinophil development but alternative developmental pathways also exist. What is needed in the art is a method of reducing the negative effects of eosinophils.